DNA Synthesis via Fluorouracil Conversion (DNA Synthesis (5-FU))

Inhibition of DNA synthesis through the action of 5-fluorouracil (5-FU), a widely used chemotherapeutic agent. 5-FU is a pyrimidine analog and pro-drug that, after intracellular conversion, disrupts both DNA and RNA metabolism in rapidly dividing cells. The most critical metabolite for DNA synthesis inhibition is FdUMP. FdUMP forms a stable ternary complex with thymidylate synthase (TS) and the folate cofactor N^5–10-methylenetetrahydrofolate. This inhibits TS, blocking the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), which is essential for synthesizing thymidine nucleotides required for DNA replication. Inhibition leads to depletion of deoxythymidine triphosphate (dTTP), causing imbalances in nucleotide pools and resulting in faulty or incomplete DNA replication. FdUTP can be incorporated directly into DNA by polymerases as a fraudulent base, while other metabolites can be incorporated into RNA, disrupting its processing and function. The disruption in nucleotide balance causes cell cycle arrest at G1/S phase and triggers apoptosis due to irreparable damage during attempted cell division.

Other names

5-Fluorouracil mechanism of action5-FU mechanism of actionThymidylate Synthase Inhibition (indirectly via 5-FU)

5-Fluorouracil (5-FU) is converted to active metabolites (FdUMP, FUMP) that inhibit thymidylate synthase (TS) and are misincorporated into nucleic acids, leading to DNA and RNA dysfunction and cell death.